From Southern Medical Journal

Endometrial Adenocarcinoma and Polycystic Ovary Syndrome: Risk Factors, Management, and Prognosis

Jennifer L. Elliott, MD, Sarah L. Hosford, MD, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Atlanta Medical Center, Atlanta, Ga; Rita I. Demopoulos, MD, Department of Pathology, New York University School of Medicine, New York, NY; Mark Perloe, MD, E. Scott Sills, MD, Division of Reproductive Endocrinology and Infertility, Atlanta Medical Center, Atlanta, Ga

Posted: 05/01/2001; South Med J. 2001;94(5) 2001 Lippincott Williams & Wilkins

AbstractThis report presents the development of endometrial adenocarcinoma after diagnosis of polycystic ovary syndrome (PCOS) in three premenopausal women. Such cases illustrate the increased potential for endometrial hyperplasia and malignancy in the setting of chronic anovulation associated with PCOS and underscore the need for prompt identification and treatment. Attention to endometrial thickness (as measured by transvaginal sonogram) and elevated insulin level (as measured by fasting plasma insulin) can improve clinical surveillance of both conditions and preserve reproductive potential for women with PCOS.

IntroductionAdenocarcinoma of the endometrium is an uncommon malignancy among women of reproductive age.[1] When this malignancy occurs in younger women, a substantial number of affected patients are anovulatory. A leading cause of chronic oligo-ovulation or anovulation is polycystic ovary syndrome (PCOS),[2] which is frequently encountered in primary care practice. In fact, the coexistence of these two clinical entities confers a good prognosis, since some investigators have reported that endometrial lesions developing in the context of PCOS have a relatively low propensity for malignant transformation.[3] In this report, we describe three such cases of PCOS and endometrial adenocarcinoma and propose a strategy for early diagnosis, screening, and treatment.Case Reports

Case 1A 46-year-old obese woman presented a 12-year history of menorrhagia, hirsutism, and secondary infertility. Since a spontaneous conception and uncomplicated delivery at age 18, she had been unable to conceive. Her menses were erratic and irregular, with an intermenstrual interval of up to 360 days. Office endometrial biopsy showed moderately differentiated endometrial adenocarcinoma. Abdominopelvic computed tomography (CT) showed the uterus to be slightly enlarged. Findings on chest x-ray film, barium enema examination, Pap test, and endocervical curettage were normal.

Two weeks after presentation, the patient had exploratory laparotomy, pelvic fluid cytology sampling, total abdominal hysterectomy/bilateral salpingo-oophorectomy (TAH-BSO), omentectomy, and para-aortic/pelvic lymph node sampling. At surgery, both ovaries were found to be grossly enlarged and polycystic. Formal staging revealed stage IIIA, grade 3 endometrial adenocarcinoma (Figure), since a metastatic implant was present on the left ovary. Qualitative immunohistochemical staining of endometrium was positive for both estrogen and progesterone receptors. Postoperative chemotherapy consisted of three cycles of intravenous cisplatin and doxorubicin (Adriamycin), followed by pelvic irradiation (4,500 cGy). Three additional cycles of cisplatin and Adriamycin were administered 4 weeks after radiotherapy. The patient was without evidence of disease 4 months after treatment and had a fasting insulin value of 40 mu/mL.

(Enlarge Image) Figure. (Case 1) Endometrium showing focal areas of poorly differentiated endometrioid adenocarcinoma, obtained at D&C from a woman with chronic anovulation and polycystic ovary syndrome. This grade 3 lesion is characterized by markedly enlarged nuclei with prominent nucleoli. (Hematoxylin-eosin stain, original magnification x 400)

Figure. (Case 1) Endometrium showing focal areas of poorly differentiated endometrioid adenocarcinoma, obtained at D&C from a woman with chronic anovulation and polycystic ovary syndrome. This grade 3 lesion is characterized by markedly enlarged nuclei with prominent nucleoli. (Hematoxylin-eosin stain, original magnification x 400)Case 2A 29-year-old obese nullipara had had primary infertility for 8 years. An infertility evaluation 6 years earlier suggested the diagnosis of PCOS. She was menstruating about every 4 months but never spontaneously, since cyclic progesterone was routinely used to induce menses. At presentation, the patient reported her last use of cyclic progesterone as "about 3 years ago." She described a gradual increase in vaginal bleeding over 14 months. Transvaginal ultrasonography showed endometrial thickness of 16 mm. Endometrial biopsy showed mixed hyperplasia. Further evaluation revealed normal results of an overnight dexamethasone suppression test, a fasting insulin of 22 mu/mL, a luteinizing hormone/follicle-stimulating hormone ratio of 1.5, and normal serum androgen levels.

Because of the patient's relative hyperinsulinemia and her strong desire to conceive, hysteroscopy and dilatation and curettage were done. Endometrial curettage showed complex atypical hyperplasia, and the patient was given megesterol acetate (80 mg twice daily) for 3 months; she also received metformin. Another curettage was done after 3 months of progesterone therapy to assess the effects of treatment. This curettage revealed a focus of grade 1 endometrial adenocarcinoma. The patient elected to proceed with definitive therapy and had exploratory laparotomy, pelvic fluid cytology assessment, and TAH/BSO. At operation, the ovaries appeared grossly polycystic, and formal staging identified stage IA, grade 1 endometrial adenocarcinoma. Perioperative recovery was uncomplicated. Although asymptomatic for 15 months after surgery, the patient has regular surveillance for disease recurrence.

Case 3A 28-year-old nullipara was seen because of irregular menses and weight gain, both symptoms gradually worsening over the past 10 years. Her medical history was incomplete, but records describing endometrial curettage in 1987 suggested "uterine polyps." The patient was hospitalized in 1990 for uncontrollable vaginal bleeding, and received a blood transfusion. Posthospitalization follow-up was poor, and the patient failed to continue taking oral contraceptive pills as prescribed for menorrhagia.

Persistent bleeding eventually led her to seek medical care, and in 1993 an office endometrial biopsy revealed grade 1 endometrial adenocarcinoma. Both hormone therapy and hysterectomy were carefully discussed with the patient; she elected the latter, and TAH/BSO, pelvic washings, para-aortic lymph node sampling, and omental biopsy were done without complication. Ovarian hyperthecosis consistent with PCOS was noted on microscopic evaluation. The uterus showed well-differentiated endometrial adenocarcinoma with focal myometrial invasion only (stage IB, grade 1). A standard estrogen replacement regimen was prescribed, and she had oncologic follow-up every 4 months for the first year. The patient had semiannual assessments in the second postoperative year, during which time non-insulin-requiring diabetes mellitus developed. There was no evidence of recurrent disease at 5 years.Information from Industry Principles in Practice: Pain Assessment and Treatment Strategies Participate in an interactive study featuring expert commentary from Dr. Matt Rosenberg Launch the activity DiscussionCarcinoma of the endometrium is the most common gynecologic malignancy in the United States. Some 3% of women will have this malignancy during their lifetime, and the majority of these will be postmenopausal. When endometrial carcinoma does develop before age 40, it is usually foreshadowed by chronic obesity and/ or anovulation.[4] Since the pioneering work of Cairns et al,[5] clinicians have appreciated the higher incidence of endometrial adenocarcinoma in the presence of anovulatory conditions and unopposed estrogen. Infertility, obesity, hirsutism, and diabetes often are responsible for general medical attention for such patients, but the insulin-resistant hyperinsulinemia component is less well appreciated.

The leading cause of anovulatory infertility in clinical practice today is PCOS.[6] This syndrome represents a form of functional ovarian hyperandrogenism affecting about 10% of all women of reproductive age.[7] A multisystem endocrine disorder, PCOS is characterized by menstrual irregularity, infertility, obesity, hirsutism, acanthosis nigricans, and insulin insensitivity.[8] Importantly, relative hyperinsulinemia is a prominent feature of both PCOS and endometrial carcinoma.[9,10] Our three cases illustrate the intersection of this important endocrinopathy and a potentially lethal gynecologic cancer.

Multiple mechanisms may be responsible for the increased risk of endometrial cancer in the context of PCOS. To be sure, endometrial carcinoma need not be associated with abnormally high estrogen or insulin levels. Yet, the chronic anovulatory or oligo-ovulatory state of PCOS is characterized by high estrogen (and insulin) but little or no progestogen activity, with resultant endometrial hyperplasia. The fact that tonically elevated insulin up-regulates estrogen-producing aromatase enzyme systems in endometrial glands and stroma[11] yields additive and deleterious results for the woman who is both hyperinsulinemic and anovulatory. Research has implicated these two derangements as fundamental in classic PCOS.[12] Thus, for a woman who has not had hysterectomy and who has insulin resistance and chronic anovulation (ie, PCOS), endometrial hyperplasia represents a common end-point of two distinct pathophysiologic processes.

Measurement of fasting plasma insulin has been proposed as a sensitive and cost-effective method of screening for hyperinsulinemia.[13] Fasting insulin levels were available for two of these anovulatory women, but the value obtained was relatively high when judged against noninsulinoma standards.[14] Once present, endometrial hyperplasia advances to frank endometrial carcinoma in as many as 30% of cases.[3] In vitro studies of insulin and insulin-like growth factors (eg, IGF-1) offer evidence explaining why this may occur, since these agents have been shown to act as potent mitogens in specific cell subpopulations. Indeed, endometrial cancer cell lines demonstrate an accelerated growth rate in the presence of insulin.[15]

For women with an intact uterus, combination hormone therapy (estrogen plus progesterone) is an important part of endometrial cancer risk reduction. Among women receiving exogenous estrogen therapy, women with diabetes are at a higher risk for the development of endometrial carcinoma than those without diabetes.[16] The use of cyclic or continuous progesterone to oppose estrogen in anovulatory women has been shown to lower the risk of endometrial malignancy. Administration of orally active insulin-modifying drugs in patients with PCOS might also attenuate this risk via alternate pathways, though this conclusion awaits formal validation. Nevertheless, limited but consistent data have shown insulin-lowering agents to be effective in correction of tonic hyperinsulinemia and restoration of normal ovulatory function in some women.[8,12]

In our practice, the routine evaluation of a woman suspected of having PCOS includes a fasting insulin measurement and transvaginal ultrasonography. Since early recognition of endometrial adenocarcinoma is improved by these measures, they are done regardless of the patient's age, tubal patency status, or desire to achieve pregnancy. While an important goal of sonography is to document enlarged, polycystic, or otherwise abnormal ovaries, information about intrauterine contour and endometrial thickness also derives from this evaluation. In cases of PCOS in chronically anovulatory women of reproductive age, we perform office endometrial sampling (biopsy) when the endometrial thickness is >10 mm. With attention to the common features of PCOS, this targeted evaluation can identify those patients with relative hyperinsulinemia and increased risk for endometrial hyperplasia. Reducing the risk of endometrial carcinoma may be facilitated by normalization of insulin metabolism and ovulation. Some investigators have reported the prognosis for future fertility among PCOS patients receiving monotherapy for hyperinsulinemia as encouraging.[8,17] Improvements in weight management, acne, hirsutism, reduced serum androgens, and cycle regularity after this clinical management strategy have also been reported.[18,19] Early detection of endometrial hyperplasia in the setting of PCOS may reduce the risk of gynecologic malignancy, and early detection is central in the preservation of reproductive potential.